Cyanophenyl derivatives

专利摘要:
The present invention relates to a novel piperazino-substituted cyanophenyl derivative in which a substituted carbamoyl group or a substituted sulfamoyl group having aryl or hetero ring which may have a substituent is bonded to a nitrogen atom on the piperazin ring will be. The compound of the present invention has an anti-androgen action and is useful for preventing or treating prostate cancer, hyperplasia of the prostate, etc.
公开号:KR20010075268A
申请号:KR1020017003629
申请日:1999-09-21
公开日:2001-08-09
发明作者:다니구치노부아키；기노야마이사오；가미쿠보다카시；도요시마아키라；사미즈기요히로；가와미나미에이지；이마무라마사카즈；모리토모히로유키；마쓰히사아키라；히라노마사아키；미야자키요지；노자와에이스케；오카다미노루；고토쿠히로시；오타미쓰아키
申请人:오노다 마사요시；야마노우치세이야쿠 가부시키가이샤；
IPC主号:

专利说明:

Cyanophenyl derivatives < RTI ID = 0.0 >
[2] Androgen, a type of steroid hormone, is secreted from the testes or adrenal cortex and causes male hormone action. When androgens are incorporated into target cells, they act on androgen receptors, and the receptors to which androgens are bound form dimers. These dimers are then bound to the androgenic reaction factors on the DNA to promote the synthesis of m-RNA, thereby inducing a protein responsible for androgenic action (see Prostate Suppl., 6, 1996, 45-51, Trends in Endocrinology and Metabolism, 1998, 9 (8), 317-324].
[3] Diseases in which androgens become hater factors include prostate cancer, hyperplasia of the prostate, menstruation, hirsutism, baldness, acne, and seborrhea. Therefore, antiandrogens have been used for the treatment of diseases in which androgens are involved.
[4] As anti-androgen agents currently in clinical use, compounds having a substrate-like steroid skeleton and compounds having a non-steroid skeleton are known. Chromarninone acetate and the like are known as the former, but these compounds are known to cause significant side effects such as lowering of the libido due to insufficient separation of action with other steroids having similar structures, resulting in fluctuation of blood hormone levels : Jpn. J. Clin. Oncol., 1993, 23 (3), 178-185.
[5] On the other hand, as a compound having a non-steroidal skeleton, acyl groups such as flutamide (Japanese Patent Application Laid-Open No. 49-81332), bicalutamide (see GB 8221421 and WO 95/19770) Anilide derivatives are known, but they do not have sufficient anti-androgenic action. Thus, combination therapy with LH-RH agonists is common in the treatment of prostate cancer (Nipponrinsho, 1998, 56 (8), 2124-2128).
[6] Examples of compounds having a piperazinoanianophenyl skeleton include those having oxytocin and vasopressin receptor antagonistic activity in WO 95/25443, substances exhibiting 5HT receptor antagonism in WO 96/02525, Substances as an interaction inhibitor, substances as preparation intermediates for cell adhesion inhibitors in WO 97/2245, substances having anti-cancer activity in WO 98/00402 and WO 98/21648, Are not disclosed or suggested at all.
[7] DISCLOSURE OF INVENTION
[8] An object of the present invention is to provide a novel cyanophenyl derivative and a salt thereof having a strong antiandrogenic action, and to provide a medicament containing them.
[9] The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems associated with conventional antiandrogenic agents. As a result, it has been surprisingly found that a novel cyanophenyl derivative having a substituted carbamoyl group or a substituted sulfamoyl group bonded thereto has a strong antiandrogen And has a good oral activity, and has completed the present invention.
[10] That is, the present invention relates to a cyanophenyl derivative of the formula (I) or a salt thereof.
[11]
[12] In the above formula (I)
[13] R is a cyano or nitro group,
[14] R ¹ is a hydrogen atom, a halogen atom, cyano, halogeno lower alkyl, nitro, carboxyl, lower alkyl, R ⁶ -A-, R ⁷ -S (O) _p- , Lower alkyl-OC (= O) - group,
[15] R ² , R ³ and R ⁴ are the same or different and represent a hydrogen atom, a lower alkyl group, a carbamoyl group which may be substituted by one or two lower alkyl groups, a lower alkyl-C (= O) (= O) - group, R ² and R ³ are bonded to any carbon atom on the ring,
[16] R ⁵ is selected from the group consisting of lower alkyl, aryl-lower alkyl-O-, carboxyl, lower alkyl-O-C (= O) -, an amide which may be substituted with one or two lower alkyl groups, or a ring or a cycloalkyl ^{group, N (R 13) R 14} - is a lower alkyl -O-, only when m is 1, R ⁴ and R ⁵ are integrally 5 members which may have other hetero atom or a 6-membered heteroaryl Can form a ring,
[17] R ⁶ is halogeno lower alkyl or aryl, N (R ⁹⁾ and R ^10, 0H or lower alkyl which may be substituted with a lower alkyl -O-,
[18] R ⁷ is lower alkyl, aryl or N (R ¹¹ ) R ¹² -
[19] R ^8, R ^9, R ^10, R ^11, R ^12, R ¹³ and R ¹⁴ is hydrogen, lower-alkyl or aryl, with the proviso that R ⁶ and R ^8, R ⁹ and R ¹⁰ or R ¹³ and R ¹⁴ are integral respectively To form a nitrogen-containing cycloalkyl which may have another heteroatom and may have a substituent,
[20] k or n is 1, 2 or 3,
[21] m is 0 or 1,
[22] p is 0, 1 or 2,
[23] A is an oxygen atom or NR < ⁸ >
[24] X is -C (= O) -, -C (= S) - or -S (O) ₂ - group, and
[25] Y is a bond, lower alkylene, -C (= O) - or -S (O) ₂ - group, provided that when R ⁵ is a lower alkyl group, Y is a group other than lower alkylene,
[26] Z ₁ or Z ₂ are the same or different and each is CH or a nitrogen atom, provided that when R ¹ is a hydrogen atom, at least one of R ² and R ³ is lower alkyl.
[27] Preferably, the cyanophenyl derivative or a salt thereof according to claim 1, wherein R is a cyano group,
[28] Also preferably, R ¹ is a halogen atom, cyano, halogeno lower alkyl, nitro or lower alkyl-O-, at least one of R ² and R ³ is a lower alkyl group, R ⁴ is a hydrogen atom or a lower alkyl group R ⁵ is an aryl, heterocyclic or cycloalkyl group which may have a substituent, k is 2, n is 1, m is 1, X is a -C (= O) - group, Y is a bond, The cyanophenyl derivative or a salt thereof according to claim 1, wherein Z ₁ or Z ₂ is both CH,
[29] More preferably, the substituent of the aryl, heterocyclic or cycloalkyl group which may have a substituent on R ⁵ is a halogen atom, halogeno lower alkyl, lower alkyl, lower alkyl-O-, lower alkyl-S-, lower alkyl-S (O) -, lower alkyl-S (O) ₂ -, sulfamoyl which may be substituted by one or two lower alkyl, halogeno lower alkyl-O-, cyano, nitro, oxo Which may be substituted by one or two lower alkyl or lower alkyl-C (= O) - or lower alkyl-OC (= O) -, Which is a group selected from the group consisting of amino, aryl-O-, amino-O-, carbamoyl which may be substituted by lower alkyl, carboxyl, lower alkyl-OC (= O) -, heterocycle and OH group Or a cyanophenyl derivative according to claim 2,
[30] Most preferably, (2R, 5S) -4- (4-cyano-3- trifluoromethylphenyl) -N- (6-methoxy-3-pyridyl) -2,5-dimethylpiperazin- (2R, 5S) -N- (2-amino-4-pyrimidyl) -4- (4-cyano-3- trifluoromethylphenyl) -2,5-dimethylpiperazin- Carboxamide, (2R, 5S) -4- (4-cyano-3-trifluoromethylphenyl) -2,5-dimethyl-N- (6-trifluoromethyl- (2R, 5S) -4- (4-cyano-3-trifluoromethylphenyl) -N- (2- fluoro-4- pyridyl) -2,5-dimethylpiperazine- Carboxamide and (2R, 5S) -N- (2-bromo-4-pyridyl) -4- (4- cyano-3- trifluoromethylphenyl) -2,5- dimethylpiperazine- 1-carboxamide, or a salt thereof,
[31] Another object of the present invention is a pharmaceutical composition comprising as an active ingredient a cyanophenyl derivative of the formula (I) or a salt thereof,
[32] Preferably, an anti-androgen agent comprising the cyanophenyl derivative of the formula (I) or a salt thereof as an active ingredient,
[33] More preferably, a cyanophenyl derivative of the formula (I) or a pharmaceutically acceptable salt thereof is a therapeutic agent for a disease in which the androgen is an effective ingredient, and the androgen is a hater factor include prostate cancer, Malaise, hirsutism, baldness, ache and boredom.
[34] Most preferably, the composition is a pharmaceutical composition for the treatment of prostate cancer and enlargement of the prostate comprising the cyanophenyl derivative of the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
[35] The compound of formula (I) will be described as follows.
[36] In the definition of the formulas herein, unless otherwise stated, the term " lower " means a straight or branched chain carbon chain having from 1 to 6 carbon atoms.
[37] R ² or R ³ is bonded to any of the same or different carbon atoms on the saturated ring containing two nitrogen atoms.
[38] The aryl, heterocyclic or cycloalkyl group which may have a substituent group may have 1 to 3 substituents on the ring, preferably a halogen atom, halogeno lower alkyl, lower alkyl, lower alkyl-O-, lower alkyl-S -, lower alkyl-S (= O) -, lower alkyl-S (O) ₂ -, sulfamoyl which may be substituted by one or two lower alkyl, halogeno lower alkyl-O-, cyano, (= O), lower alkyl-C (= O) -, aryl-C (= O) -, one or two lower alkyl or lower alkyl- - (lower alkyl) amino, aryl-O-, amino-O-, carbamoyl which may be substituted by lower alkyl, carboxyl, lower alkyl-O-C (= O) -, Or an OH group.
[39] The "lower alkyl" is preferably a linear or branched lower alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -Butyl, n-pentyl, n-hexyl and the like.
[40] Examples of the substituent of the lower alkyl group -O- which may have a substituent include substituents such as an aryl group.
[41] The "lower alkylene" is preferably a straight or branched chain lower alkylene group having 1 to 6 carbon atoms, and examples thereof include methylene, ethylene, propylene, isopropylene, butylene, pentamethylene, hexamethylene, Preferably an alkylene having 1 to 3 carbon atoms.
[42] The "aryl" is preferably an aromatic hydrocarbon group having 6 to 12 carbon atoms, and examples thereof include phenyl, α-naphthyl, β-naphthyl, biphenyl and the like. And more preferably 6 to 10 carbon atoms.
[43] Examples of the " halogen atom " include fluorine, chlorine, bromine and iodine atoms.
[44] The lower alkyl group of the "halogeno lower alkyl" is preferably the above-mentioned C _1-6 alkyl group, and examples of the halogeno C _1-6 alkyl group include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl , Dichloromethyl, trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloroethyl, 2,2- 2-trichloroethyl, 2-bromoethyl, 2-iodoethyl and the like, and trifluoromethyl is preferable.
[45] As the "cycloalkyl group", a 3- to 8-membered cycloaliphatic hydrocarbon group having 3 to 10 carbon atoms is preferable, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
[46] The "heterocycle" is a 5- or 6-membered heteroaryl group or saturated heterocycle containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, or a divalent heteroaryl group condensed with a benzene ring or other heterocycle And examples of the heteroaryl include pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, thiophene, thiopyran, furan, pyran, dioxolane, thiazole, isothiazole, Pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, Examples of the condensed heteroaryl include indole, isoindole, indazole, quinoline, quinazoline, quinoxaline, isoquinoline, benzimidazole, benzothiophene, benzothiophene, , Benzothi Pyridopyridine, phthalazine, naphthyridine, indolizine, purine, quinolizine, cinnolin, isocoumarin, chroman, and the like can be mentioned . Is preferably a 5-or 6-membered heteroaryl group such as pyridine, pyrimidine, thiophene or furan containing 1 or 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
[47] Means that, when m is 1, R ⁴ and R ⁵ may be monosubstituted to form a 5-membered or 6-membered heterocycle which may have another heteroatom. "In addition to the nitrogen atom to which R ⁴ is bonded, A 5-membered or 6-membered heteroaryl group or a saturated heterocyclic ring containing 1 to 3 hetero atoms selected from an atom and a sulfur atom, and may have a substituent such as an oxo group. Specific examples of the heteroaryl include pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole and the like. Examples of the saturated hetero ring include pyrrolidinyl, piperidinyl, Morpholyl group, thiomorpholyl group, 1,4-diazabe group, thiomorpholine-1-oxide group, thiomorpholine-1,1-dioxide group, 1,4-oxazepan group and the like. Is preferably a 5-membered or 6-membered saturated heterocycle containing one hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to the nitrogen atom to which R ⁴ is bonded, more preferably a thiomorpholino group.
[48] "R ⁶ and R ^8, R ⁹ and R ¹⁰ or R ¹³ and R ¹⁴ may be integrally have the other hetero atom and nitrogen which may have a substituent containing cycloalkyl each" is R ⁶ and R ^8, R ⁹ and R ¹⁰ or R ¹³ and R ¹⁴ is a is a 5 or 6 membered saturated, which may contain one hetero atom selected from nitrogen atom, oxygen atom and sulfur atom as other hetero atoms other than the nitrogen atom bonded heterocycle, an oxo group , Lower alkyl, aryl, and the like. Preferable are pyrrolidino, piperidino, morpholino, piperazino, thiomorpholino group.
[49] In the case of a compound having a tertiary amine or sulfide in the compound of the present invention, the nitrogen atom or sulfur atom may be oxidized in a suitable oxidation step and all of these oxided derivatives are included.
[50] The compound (I) of the present invention has a geometric isomer based on an amide bond. Depending on the type of the substituent, there may be one or more sub-centers such as carbon, nitrogen, sulfur and the like, or an axially reducing agent, and the optical isomers such as the (R) Isomers and the like. Further, depending on the kind of the substituent, there are double bonds, and therefore there are geometrical isomers such as a cis body and a trans isomer based on the (Z), (E), and cyclohexane. The present invention encompasses all of the separated isomers or mixtures thereof.
[51] The compounds of the present invention form salts. Specifically, it is an acid addition salt with an inorganic acid or an organic acid, a salt with an inorganic base or an organic base, and a pharmaceutically acceptable salt is preferable. Specific examples of the salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid, organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, (For example, sodium, potassium, sodium, potassium, etc.) or an acidic amino acid (for example, aspartic acid or glutamic acid) And salts with organic bases such as methylamine, ethylamine and ethanolamine) or basic amino acids (such as lysine and ornithine), and the like. It may also be a quaternary ammonium salt. The quaternary ammonium salt is specifically a lower alkyl halide, a lower alkyl triflate, a lower alkyl tosylate or a benzyl halide, preferably methyl iodide or benzyl chloride.
[52] In addition, the compound of the present invention can form solvates and crystalline polymorphs with hydrates, ethanol and the like.
[53] (Recipe)
[54] 1st recipe
[55]
[56] (In the above formula, the symbols are as defined above.)
[57] This process is a process for preparing the compound (I) of the present invention by reacting a substituted amine of the formula (II) or a salt thereof with a compound of the formula (III) or a reactive derivative thereof and removing the protecting group when a protecting group is present.
[58] Examples of the reactive derivative of the compound (III) include conventional esters such as methyl esters, ethyl esters, isobutyl esters, and tert-butyl esters of carboxylic acids; phenyl esters such as p-nitrophenyl ester; Acid halides such as acid chloride, acid bromide; Acid azide; An active ester obtained by reacting a phenolic compound such as 2,4-dinitrophenol or the like with an N-hydroxyamine compound such as 1-hydroxysuccinimide or 1-hydroxybenzotriazole (HOBt); Symmetric acid anhydride; An organic acid-based mixed acid anhydride obtained by reacting with a halocarboxylic acid alkyl ester such as alkylcarboxylate halide or the like, pivaloyl halide or the like, an organic phosphorus compound such as triphenylphosphine and an activator such as N-bromosuccinimide A mixed acid anhydride such as a mixed acid anhydride of phosphoric acid type obtained by the method; Sulfonyl chloride; Isocyanate.
[59] In addition, when the carboxylic acid is reacted as a free acid or without isolation of the active ester, it is possible to use dicyclohexylcarbodiimide (DCC), carbonyldiimidazole, diphenylphosphoryl azide, diethylphosphoryl cyanide or 1 -Ethyl-3 (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC).
[60] Particularly, in the present invention, the acid chloride method, the method of reacting with the active esterifying agent in the coexistence, and the condensation reaction with isocyanate and thioisocyanate are advantageous.
[61] In addition, the isocyanate can be synthesized from a carboxylic acid derivative such as a carboxylic acid, an amide, an acid hydrazide or the like using a known transition reaction. In the case of conversion from a carboxylic acid to an isocyanate, it is advantageous to first convert it to an acid chloride or a mixed acid anhydride, then react with sodium azide or the like to obtain an acid azide, and then convert it into isocyanate by heating or the like. In this case, diphenylphosphoryl azide (DPPA) or the like can be used to convert to isocyanate. Compound (I) can also be obtained by the action of DPPA in the presence of a carboxylic acid and a compound (II). On the other hand, the corresponding amine derivative can be reacted with a phosgene or phosgene equivalent to obtain an isocyanate. Examples of such equivalents include a combination of phosgene dimer, triphosgene, carbonyldiimidazole, di-tert-butyl dicarbonate (DIBOC) and 4- (N, N-dimethylamino) pyridine (DMAP) . The thioisocyanate can also be synthesized by using a known reaction using thiophosgene, thiocarbonyldiimidazole or the like.
[62] In addition, the corresponding amine derivative can be derivatized to an active intermediate having a leaving group represented by phenylcarbonate, and then reacted with the compound (II) to obtain the compound (I).
[63] The reaction may vary depending on the reactive derivative or the condensing agent to be used and is usually in the range of 0.1 to 10 mol% based on the total amount of the reaction mixture in the presence of halogenated hydrocarbons (e.g., dichloromethane, dichloroethane, chloroform, etc.), aromatic hydrocarbons (e.g. benzene, toluene, N, N-dimethylacetamide, N, N-dimethylacetamide, N-methylpyrrolidone or dimethyl (meth) acrylate, In an inert organic solvent such as imidazolidinone, depending on the kind of the reactive derivative, the reaction is carried out under cooling, under cooling to room temperature, or at room temperature to under heating.
[64] In addition, when the substituted amine (II) is used excessively in the reaction, or N-methylmorpholine, trimethylamine, N, N-dimethylaniline, pyridine, DMAP, picoline, lutidine, collidine, , 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or the like in the presence of a base is advantageous for smoothly proceeding the reaction. Pyridine and the like can be used as a solvent.
[65] In this case, it is preferable that the oxygen atom, the sulfur atom, and the nitrogen atom present in the molecule are bonded to the protecting group. As the protecting group, there can be mentioned, for example, "Protective Groups in Organic Synthesis", 2nd edition, written by Greene and Wuts And the like, and they can be appropriately used in accordance with the reaction conditions.
[66] Second recipe
[67]
[68] (In the above formula, the symbols are as defined above.)
[69] This process can be carried out by reacting a substituted amine of the formula (II) or a salt thereof with a reactive compound having X or an equivalent thereof, then reacting the compound with a compound of the formula (IV) .
[70] When the product is a urea derivative, as the reactive compound having X or equivalent, phosgene, phosgene dimer, triphosgene, carbonyldiimidazole or a known equivalent can be used. When the product is a sulfamide derivative, known reagents such as sulfamidosulfuryl chloride may be used.
[71] In addition, the conditions described in the first production method can be used at the time of the reaction.
[72] Third recipe
[73]
[74] (In the above formula, Q is a halogen such as fluorine, chlorine, bromine, iodine, or a leaving group such as trifluoromethanesulfonate or benzenesulfonate.)
[75] This process is a process for producing the compound (I) of the present invention by reacting a substituted amine of the formula (VI) or a salt thereof with a compound of the formula (V).
[76] In addition, when the substituted amine (VI) is excessively used in the reaction or an organic base such as N-methylmorpholine, trimethylamine, triethylamine, diisopropylethylamine, N, N-dimethylaniline, In the presence of an inorganic base (e.g., potassium carbonate, sodium carbonate, calcium carbonate, sodium hydrogen carbonate, sodium hydroxide, cesium carbonate, or the like) in the presence of a base such as picoline, lutidine, 1,8-bistrimethylaminonaphthalene or DBU There are cases where it is advantageous to proceed the reaction smoothly. Pyridine and the like can be used as a solvent. It is also appropriate to use an organometallic catalyst as a catalyst. The reaction is usually carried out in the presence of a halogenated hydrocarbon such as dichloromethane, dichloroethane or chloroform, an aromatic hydrocarbon such as benzene, toluene or xylene, an ether such as dichloromethane, Ethers, tetrahydrofuran and the like), esters (e.g. ethyl acetate and the like), alcoholic solvents (e.g. ethanol and methanol), acetonitrile, DMF, N, N-dimethylacetamide, N, N-dimethylimidazolidinone, or dimethylsulfoxide, depending on the kind of the reactive derivative, under cooling, at room temperature, or at room temperature to under heating.
[77] Fourth recipe
[78]
[79] (In the above formula, the symbols are as defined above.)
[80] This process is a process for producing the compound (I) of the present invention by alkylating or acylating the compound of the formula (I ': R ⁴ = H).
[81] In this reaction, an alkyl halide (e.g., methyl iodide, ethyl iodide, benzyl bromide, etc.), a sulfuric acid ester (e.g., dimethylsulfate etc.) or a sulfonate (e.g., methanesulfonate, methyltrifluoromethanesulfonate, etc.) The same alkylating agent can be used. Alternatively, acylating agents such as acid chlorides (e.g., acetyl chloride) or acid anhydrides (such as acetic anhydride) are used. At this time, an organic base (e.g., triethylamine, diisopropylethylamine, pyridine, lithium diisopropylamine, sodium hexamethyldisilazide and the like) or an inorganic base (e.g., sodium carbonate, potassium carbonate, calcium carbonate, sodium hydrogencarbonate , Sodium hydroxide, sodium hydride, etc.) can be used.
[82] The reaction is usually carried out in the presence of a halogenated hydrocarbon such as dichloromethane, dichloroethane or chloroform, an aromatic hydrocarbon such as benzene, toluene or xylene, an ether such as ether or tetrahydrofuran, For example, ethyl acetate, etc.), DMF, N, N-dimethylacetamide, dimethylsulfoxide and the like in a reaction-inert organic solvent under cooling, under cooling to room temperature or at room temperature to under heating.
[83] Fifth recipe
[84]
[85] (In the above formula, the symbols are as defined above.)
[86] This production process is a process for producing the compound (I) of the present invention by ring closure of the compound of the formula (VII).
[87] In this reaction, aldehydes or ketones and carbonyl equivalents such as acetal, ketal, thiocetal, etc. are used for the ring closure. The reaction can be generally carried out in an acidic or basic condition and is usually carried out in the presence of a halogenated hydrocarbon such as dichloromethane, dichloroethane or chloroform, an aromatic hydrocarbon such as benzene, toluene or xylene, In an inert organic solvent such as DMF, N, N-dimethylacetamide, dimethylsulfoxide and the like in the presence of a reactive derivative, in a reaction-inert organic solvent such as tetrahydrofuran, ether, tetrahydrofuran and the like, esters such as ethyl acetate, Is carried out at room temperature or at room temperature to under heating. Of these, organic acids such as acetic acid and trifluoroacetic acid are particularly suitable.
[88] The compound of the present invention synthesized according to the above process can be converted into the compound of the present invention according to conversion of a functional group or the like using a known reaction, and a part thereof is described in the examples.
[89] The thus-prepared compound of the present invention is isolated and purified as a free form, a salt thereof, a hydrate thereof, a solvate thereof, or a crystalline polymorph. The salt of the compound (I) of the present invention can be prepared by a salt-forming reaction of a conventional method.
[90] Isolation and purification are carried out by applying ordinary chemical operations such as extraction, concentration, distillation removal, crystallization, filtration, recrystallization, and various kinds of chromatography.
[91] The various isomers can be selectively synthesized by using appropriate starting compounds, reactants or reaction conditions, or can be separated using the difference in physical properties between isomers. For example, the optical isomer can be obtained by stereoselectively synthesizing an optically active isomer by a suitable raw material or by racemic resolution of the racemic compound (for example, by a conventional method of optically resolving a diastereomeric salt with an optically active base, followed by optical resolution) Can be induced to pure isomers.
[92] Formulations containing at least one compound of the present invention or a salt thereof as an active ingredient are usually prepared using carriers, excipients, and other additives used for formulation.
[93] The administration can be any one of oral administration by means of tablets, pills, capsules, granules, powders, liquid preparations or the like or parenteral administration by injection (for example, intravenous injection, intramuscular injection), suppository, transdermal or the like. The dose is appropriately determined according to the individual case in consideration of the symptom, the age and sex of the subject to be administered, but is usually about 0.01 to 50 mg per day for an adult in the case of oral administration and about 0.01 to 50 mg per day in an adult for parenteral administration 0.001 to 5 mg, which is administered once or twice or four times.
[94] As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, one or more active substances may be combined with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate or magnesium aluminate Mixed. The composition may contain additives other than an inert diluent such as a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a stabilizer such as lactose, or a solubilizing agent such as, for example, Glutamic acid or aspartic acid). The tablets or pills may be coated with a film of a gastric or enteric material such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like, if necessary.
[95] Liquid compositions for oral administration contain pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and contain commonly used inert diluents, for example, purified water or ethanol. Such compositions may contain, in addition to inert diluents, auxiliary agents such as wetting and suspending agents, as well as sweetening, flavoring, perfuming, preservatives.
[96] The injectable preparation for parenteral administration includes sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the aqueous solutions and suspensions include distilled water for injection and physiological saline. Examples of the non-aqueous solution and suspension include vegetable oils such as propylene glycol, polyethylene glycol and olive oil, alcohols such as ethanol, and polysorbate 80 (trade name). Such compositions may additionally contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents (e.g., lactose), and solubilizing agents (e.g., glutamic acid, aspartic acid). They are sterilized, for example, by filtration through a bacterial retention filter, blending or irradiation of a bactericide. They may also be prepared by preparing sterile solid compositions and dissolving them in a sterile water or sterile injectable solvent before use.
[97] Example
[98] Hereinafter, the present invention will be described in more detail by way of examples. The present invention is not limited to these embodiments at all. The method of producing the starting compounds used in the examples is described as a reference example.
[99] Reference Example 1-1
[100] Trans-4- (2,5-dimethylpiperazin-1-yl) -2-trifluoromethylbenzonitrile
[101] Fluoro-2-trifluoromethylbenzonitrile and 2.4 g of trans-2,5-dimethylpiperazine are dissolved in 30 ml of DMF, and the mixture is heated at 80 ° C overnight. Water is added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.3 g of the title compound from a chloroform-methanol (10: 1, v / v) eluate.
[102] Reference Examples 1-2 to 1-17 were synthesized in the same manner as in Reference Example 1-1. Their structures and physical properties are shown in Tables 1 to 3.
[103] Reference Example 2
[104] Synthesis of t-butyl 3-methylpiperazine-1-carboxylate
[105] Under ice cooling, 15 ml of a solution of DIBOC 10.9 g of tetrahydrofuran (THF) is added to 150 ml of a THF solution of 10 g of 2-methylpiperazine. After stirring overnight, the solvent is distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed and dried, and the solvent was distilled off under reduced pressure to obtain 8.94 g of the title compound as yellow oily substance.
[106] Reference Example 3
[107] butyl 4- (4-cyano-3-trifluoromethylphenyl) -3-methylpiperazine-1-carboxylate
[108] 4.46 g of t-butyl-3-methylpiperazine-1-carboxylate synthesized in Reference Example 2, 6.74 g of 4-fluoro-2-trifluoromethylbenzonitrile and 7.76 ml of diisopropylethylamine were dissolved in 50 ml of DMF Stir at 100 ° C for 2 days. The reaction solution is diluted with water, extracted with ethyl acetate, and then the organic layer is washed and dried, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (3: 1, v / v) to obtain 5.6 g of the title compound as white crystals.
[109] Reference Example 4
[110] 4- (2-methylpiperazin-1-yl) -2-trifluoromethylbenzonitrile
[111] 2.85 g of t-butyl 4- (4-cyano-3-trifluoromethylphenyl) -3-methylpiperazine-1-carboxylate synthesized in Reference Example 3 was dissolved in 50 ml of trifluoroacetic acid at 0 [ Lt; / RTI > The solvent is distilled off under reduced pressure, neutralized with a saturated aqueous solution of sodium hydrogencarbonate, extracted with ethyl acetate, and then the organic layer is washed and dried, and the solvent is distilled off under reduced pressure. The residue was purified using silica gel column chromatography and 5.6 g of the title compound was obtained as a pale yellow, white crystals from a chloroform-methanol-28% ammonia water (10: 1: 0.1, v / v / v) eluate.
[112] The properties of Reference Examples 2 to 4 are shown in Table 4.
[113] Reference Example 5-1
[114] 4- (4-Benzyl-2-ethyl-3-oxopiperazin-1-yl) -2- trifluoromethylbenzonitrile
[115] 0.94 ml of diisopropylamine is dissolved in 10 ml of anhydrous THF, and 4.5 ml of a 1.47 M butyllithium / hexane solution is added at -20 째 C, followed by stirring for 10 minutes, followed by cooling to 178 째 C. 20 ml of an anhydrous THF solution of 2 g of 4- (4-benzyl-3-oxopiperazin-1-yl) -2-trifluoromethylbenzonitrile synthesized in Reference Example 1-15 was added dropwise and stirred for 20 minutes, 0.67 ml of ethyl iodide is added. After raising the temperature to -10 DEG C, the reaction solution is poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer is washed, dried and the solvent is distilled off under reduced pressure. The residue was purified using silica gel column chromatography and 1.5 g of the title compound was obtained as a white foam from hexane-ethyl acetate (1: 1, v / v) eluate.
[116] Reference Example 5-2 and Reference Example 5-3 were synthesized in the same manner as in Reference Example 5-1.
[117] Reference Example 6-1
[118] 4- (4-Benzyl-2-ethylpiperazin-1-yl) -2-trifluoromethylbenzonitrile
[119] To a solution of 1.47 g of 4- (4-benzyl-2-ethyl-3-oxopiperazin-1-yl) -2-trifluoromethylbenzonitrile synthesized in Reference Example 5-1 in anhydrous THF 5 ml of borane-THF solution was added dropwise and stirred for 4 hours. 10 ml of methanol and 38 ml of 1N hydrochloric acid were added and stirred. The reaction mixture was concentrated under reduced pressure, and the mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. The mixture was extracted with ethyl acetate, and the organic layer was washed and dried to remove the solvent under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.67 g of the title compound as a yellow oily substance from hexane-ethyl acetate (5: 1, v / v) eluate.
[120] Reference Example 6-2 and Reference Example 6-3 were synthesized in the same manner as in Reference Example 6-1.
[121] Reference Example 7-1
[122] 4- (2-ethylpiperazin-1-yl) -2-trifluoromethylbenzonitrile
[123] 6,5 g of 4- (4-benzyl-2-ethylpiperazin-1-yl) -2-trifluoromethylbenzonitrile O synthesized in Reference Example 6-1 and 65 mg of 10% palladium- ≪ / RTI > at room temperature for 6 hours. The insoluble materials were separated by filtration using celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with chloroform-methanol-29% aqueous ammonia (10: 1: 0.1, v / v / v ) Of the title compound as a yellow oily substance.
[124] Reference Example 7-2 and Reference Example 7-3 were synthesized in the same manner as in Reference Example 7-1.
[125] Table 5 shows the structures and physical properties of Reference Examples 5-1 to 7-3.
[126] Reference Example 8
[127] Trans-4- (2,5-dimethylpiperazin-1-yl) phthalonitrile
[128] 1.52 g of 4-hydroxyphthalonitrile was dissolved in 30.0 ml of acetonitrile, 2.1 ml of triethylamine was added, and the mixture was stirred at 110 캜. 1.8 ml of anhydrous trifluoromethane sulfonic acid was added to the reaction solution, the mixture was stirred at 0 ° C for 30 minutes, then the temperature was raised to room temperature, 15 ml of DMF was added, and the mixture was stirred for 2 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried with sodium sulfate. After distilling off the solvent under reduced pressure, the residue was dissolved in 20 ml of acetonitrile, 2.30 g of 2,5-trans dimethylpiperazine was added, and the mixture was heated to reflux for 2 hours and stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and ethyl acetate (100 ml) was added to the residue. The mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound.
[129] Reference Example 9-1
[130] 1- [2- (4-cyano-3-trifluoromethylanilino) -1,1-dimethylethyl] -3- (4- fluorophenyl) urea
[131] 4- (2-Amino-2-methylpropylamino) -2-trifluoromethylbenzonitrile is dissolved in 60 ml of dichloromethane, and 0.49 ml of 4-fluorophenyl isocyanate is added dropwise and the mixture is stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with dichloromethane and dried to give 1.30 g of the title compound.
[132] The following Reference Example 9-2 is synthesized in the same manner as in Reference Example 9-1.
[133] 1- [4- (4-cyano-3-trifluoromethylanilino) butyl] -3- (4- fluorophenyl) urea
[134] Reference Example 10
[135] Benzyl 3-methylpiperazine-l-carboxylate
[136] 4 g of 2-methylpiperazine is dissolved in 40 ml of dichloromethane, and 1.71 g of benzyl chloroformate is added dropwise at -78 deg. After stirring for 1 hour, washing with water and drying, the solvent was distilled off to obtain 2.0 g of the title compound.
[137] Reference Example 11-1
[138] (2S, 5R) -4- (2,5-dimethylpiperazin-1-yl) -2-trifluoromethylbenzonitrile
[139] (+/-) - trans-4- (2,5-dimethylpiperazin-1-yl) -2-trifluoromethylbenzonitrile was dissolved in 20 ml of an ethanol-water mixed solvent, -L-tartaric acid [(-) - DIBETA] was repeatedly subjected to fractional recrystallization to obtain a salt. This salt was added to an aqueous 5N sodium hydroxide solution and the oily substance was extracted with ethyl acetate. The solvent was distilled off to obtain 2 g of the title compound.
[140] Reference Example 11-2
[141] (2R, 5S) -trans-4- (2,5-dimethylpiperazin-1-yl) -2-tricarboxylic acid was obtained by following the same procedure as in Reference Example 11-1, using (+) - dibenzoyl-D- Fluoromethylbenzonitrile is obtained.
[142] Reference Example 12-1
[143] (3S, 6R) -1-benzyl-3,6-dimethylpiperazine-2,5-dione
[144] 0.98 g of N-tert-butoxycarbonyl-L-alanine was added to a solution of 1.07 g of DCC cooled to 0 占 폚 in 50 ml of dichloromethane, and the mixture was stirred for 5 minutes. To this solution was added a solution of 1.0 g of N-benzyl-D-alanine methyl ester in 10 ml of dichloromethane, followed by stirring at room temperature for 2 days. The white precipitate is separated by filtration, washed with diethyl ether and the filtrate is concentrated. The residue was dried under reduced pressure, 30 ml of dichloromethane was added, and the mixture was cooled to 0 ° C, 5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, extracted with chloroform, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was treated with silica gel column chromatography and purified with n-hexane-ethyl acetate (1: 5, v / v) to give 10 g of the title compound as colorless oily substance.
[145] Reference Example 12-2
[146] (2R, 5S) -1-benzyl-2,5-dimethylpiperazine
[147] 0.5 g of lithium aluminum hydride was added to a solution of 1.0 g of (3S, 6R) -1-benzyl-3,6-dimethylpiperazin-2,5-dione in 30 ml of THF at 0 ° C under an argon atmosphere and the mixture was stirred overnight under heating and refluxing conditions . The reaction solution was cooled to 0 캜, 1.0 ml of water was added dropwise, 1.0 ml of a 10% sodium hydroxide aqueous solution was added dropwise, 1.0 ml of water was added again, and the mixture was stirred for 30 minutes. The precipitate was separated by filtration, washed with ethyl acetate, and then the filtrate was washed with 10% aqueous potassium carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was treated by silica gel column chromatography, and 0.75 g of the title compound was obtained as a yellow oily substance from the chloroform-methanol-28% ammonia water (25: 1: 0.1, v / v / v) eluate.
[148] Reference Example 12-3
[149] (2S, 5R) -4- (4-benzyl-2,5-dimethylpiperazin-1-yl) -2-trifluoromethylbenzonitrile
[150] To a solution of 0.63 g of (2R, 5S) -1-benzyl-2,5-dimethylpiperazine in 15 ml of pyridine was added 0.7 g of 4-fluoro-2-trifluoromethylbenzonitrile and the mixture was stirred at 90 ° C for 2 days. The reaction solution was concentrated and the residue was purified by silica gel column chromatography to obtain the title compound as a white solid in n-hexane-ethyl acetate (9: 2, v / v).
[151] Reference Example 12-4
[152] (2S, 5R) -4- (2,5-dimethylpiperazin-1-yl) -2-trifluoromethylbenzonitrile
[153] To a solution of 0.31 g of (2S, 5R) -4- (4-benzyl-2,5-dimethylpiperazin-1-yl) -2-trifluoromethylbenzonitrile in 20 ml of dichloroethane was added 1-chloroethyl chloroformate And the mixture is stirred under heating and refluxing conditions for 2 days. The reaction solution was concentrated, 20 ml of methanol was added, and the mixture was stirred under heating and refluxing for 1 day. The reaction mixture was concentrated, the residue was purified by silica gel column chromatography, and the residue was purified by chloroform-methanol (9: 1, v / v) to obtain 0.19 g of the title compound as yellow oily substance.
[154] The nonlinearity of the present compounds and the retention time on an optically active HPLC column (Daicel Gakugei Kogyo Co., CHIRALCEL 0DH) are in agreement with those obtained by using (-) - DIBETA in Reference Example 11-1.
[155] Reference Example 13
[156] 6-Trifluoromethylnicotinic acid
[157] 2.9 g of 5-cyano-2-trifluoromethylpyridine and 30 ml of concentrated hydrochloric acid are stirred at 90 DEG C for 13 hours. The reaction solution is cooled to room temperature, water is added, and the pH is adjusted to 2 to 3 with 28% ammonia water. The precipitated crystals were collected by filtration and then washed with water to obtain 2.22 g of the title compound.
[158] Reference Example 14
[159] 2-Methoxycarbonylisonicotinic acid
[160] Pyridine-2,4-dicarboxylic acid (5.0 g) in methanol (50 ml), concentrated sulfuric acid (1.7 ml) was added and the mixture was refluxed for 1 hour and 10 minutes. After cooling, the mixture was poured into ice water and stirred at 5 ° C for 3 hours. The precipitated white solid was filtered off. 5.7 g of this product is dissolved in 100 ml of methanol by heating, cooled and then stirred at room temperature. The precipitated white solid was collected by filtration to obtain 2,5 g of the title compound.
[161] Reference Example 15
[162] 3-Cyano-6-cyclopropyl-2-oxo-1,2-dihydropyridine-4- carboxylic acid ethyl ester
[163] To a solution of 41.9 g of 2,4-dioxocyclopropanebutyric acid ethyl ester in 300 ml of ethanol was added 19.2 g of 2-cyanoacetamide under stirring at room temperature. The temperature is raised to 65 ° C to completely dissolve the reagent, and 7.4 ml of piperazine is added dropwise. After 1 hour, the mixture is cooled to room temperature and stirred for 15 hours and 30 minutes. Precipitated crystals were collected by filtration and then washed with diethyl ether to give 24.1 g of the title compound. These compounds are used in the next reaction without further purification.
[164] Reference Example 16
[165] 2-Cyclopropyl-6-methoxyisonicotinic acid methyl ester
[166] 3-Cyano-6-cyclopropyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid ethyl ester A solution of 12.0 g of concentrated hydrochloric acid in 100 ml of water is heated to reflux for 5 hours and 40 minutes. After cooling, the solvent was distilled off and 15.0 g of crude carboxylic acid was obtained. 13.9 g of the present compound is suspended in 250 ml of benzene, and 7.7 ml of methyl iodide and 19.9 g of silver carbonate are added in this order at room temperature with stirring, and the temperature is raised to 50 ° C. After 74 hours, the reaction mixture was cooled to room temperature, filtered using celite, and then the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 957 mg of the title compound from ethyl acetate-hexane (1: 6, v / v) eluate.
[167] Reference Example 17
[168] 4-Amino-2-bromopyridine
[169] 8.78 g of 2-bromo-4-nitropyridine N-oxide, 11.2 g of iron powder and 1.2 g of ammonium chloride were sequentially added to 450 ml of a 67% aqueous solution of ethanol, and the mixture was heated under reflux for about 30 minutes. An insoluble matter is removed by filtration, and the obtained filtrate is distilled off under reduced pressure. An appropriate amount of a saturated aqueous solution of sodium hydrogencarbonate is poured into the resulting residue and extracted with ethyl acetate. The organic layer was washed with water and dried. The crude product formed by distillation under reduced pressure was purified by silica gel column chromatography to obtain the title compound as a pale yellow crystal from chloroform-methanol-28% aqueous ammonia (200: 9: 1, v / v / v) 4.4 g.
[170] Reference Example 18
[171] 4-Amino-2- (t-butoxycarbonylamino) pyrimidine
[172] 5.52 g of 2,4-diaminopyrimidine was added to 150 ml of t-butanol and dissolved by heating to about 60 DEG C, followed by cooling to room temperature, followed by the addition of 12.38 g of DlB0C, and stirring at room temperature for about 3 days . The crude product formed by vacuum distillation removal was purified by silica gel column chromatography and 7.02 g of the title compound as a white crystal was obtained from the chloroform-methanol-28% ammonia water (200: 9: 1, v / v / v) eluate.
[173] Reference Example 19
[174] 2-Cyano-4-pyridylcarbamic acid tert-butyl ester
[175] 1.8 ml of triethylamine and 2.8 ml of DPPA are added to a solution of 1.5 g of 2-cyanoisonicotinic acid in 100 ml of t-butanol, with stirring at room temperature, and the mixture is heated under reflux for 4 hours and 25 minutes. After cooling to room temperature, water is added to the reaction solution, which is then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, dried using anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 1.34 g of the title compound from the ethyl acetate-hexane (1: 2, v / v) eluate.
[176] Reference Example 20
[177] 2-Acetyl-4-pyridylcarbamic acid tert-butyl ester
[178] To a solution of 1.58 g of 2-cyano-4-pyridylcarbamic acid tert-butyl ester in 30 ml of THF was added 7.2 ml of a solution of methylmagnesium bromide-3M diethyl ether under ice-cooling with stirring. After 40 minutes, 1N aqueous hydrochloric acid solution was added, cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1.16 g) from an ethyl acetate-hexane (1: 2, v / v) eluate.
[179] Reference Example 21
[180] 5-Aminomethyl-2-methoxypyridine
[181] 1.00 g of 5-cyano-2-methoxypyridine was dissolved in 30 ml of ethanol and 10 ml of 28% ammonia water, 1 g of Raney nickel was added, and the mixture was stirred under hydrogen atmosphere at normal pressure for 4 hours. After filtration using celite, the solvent was distilled off to obtain 962 mg of the title compound.
[182] Reference Example 22
[183] 2- (1-Imidazolyl) pyridine N-oxide
[184] 0.76 g of imidazole is added to 7 ml of N, N-dimethylformamide, 0.2 g of 90% lithium hydride is added under ice-cooling, and the mixture is stirred for 40 minutes. Then, 2.17 g of 2-bromopyridine N-oxide hydrochloride was gradually added, stirred at room temperature for about 1 hour, heated at 80 占 폚 for about 1 hour, and then the solvent was distilled off. The resulting mixture was filtered through a silica gel column The residue was chromatographed and eluted with chloroform-methanol-28% aqueous ammonia (10: 0.9: 0.1, v / v / v) to give 1.21 g of the title compound as pale yellow crystals.
[185] Reference Example 23
[186] 2- (1-Imidazolyl) -4-nitropyridine N-oxide
[187] 3.22 g of 2- (1-imidazolyl) pyridine N-oxide was added to 7.6 g of concentrated sulfuric acid, and a mixture of 5.2 g of fuming nitric acid and 2.6 g of concentrated sulfuric acid was gradually added dropwise under ice cooling. Lt; / RTI > The reaction solution was cooled, poured into 150 g of ice-cold water, neutralized with potassium carbonate, and extracted with 300 ml of ethyl acetate. The organic layer was dried and then concentrated. The obtained mixture was treated with silica gel column chromatography and eluted with chloroform-methanol-28% aqueous ammonia (200: 0.9: 0.1, v / v / v) to obtain 0.12 g.
[188] Reference Example 24
[189] 4-Amino-2- (1-imidazolyl) pyridine
[190] 0.12 g of 2- (1-imidazolyl) -4-nitropyridine N-oxide was suspended in 14 ml of a 70% aqueous ethanol solution, and then 0.32 g of iron powder and 20 mg of ammonium chloride were added successively, followed by heating at 100 ° C for about 20 minutes do. Immediately after the reaction, the insoluble matter was removed by filtration, and the obtained filtrate was distilled off under reduced pressure to obtain 0.1 g of the title compound.
[191] Reference Example 25
[192] 2-Aminomethyl-6-chloropyridine
[193] Raney nickel (3.3 g) was suspended in ethanol (30 ml), and 1.42 g of 2-cyano-6-chloropyridine and 10 ml of 28% ammonia water were added. The mixture was stirred at room temperature for 4 hours in a hydrogen stream. The reaction mixture is filtered using celite and the filtrate is concentrated to give 1.38 g of the title compound as a mixture.
[194] Reference Example 26
[195] Methyl 2-morpholinoisonicotinate
[196] 5.0 g of 2-chloro-isonicotinic acid and 6.91 g of morpholine are suspended in 16 ml of isopropanol and stirred in a sealed tube at 150 占 폚 for 27 hours. After distilling off the solvent, 70 ml of methanol and 5 ml of concentrated sulfuric acid are added, and the mixture is heated under reflux for 6.5 hours. The solvent is distilled off, dissolved in chloroform, and washed with a saturated aqueous solution of sodium hydrogencarbonate. The solvent was distilled off, and the resulting mixture was then subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (4: 1, v / v) to give 4.42 g of the title compound.
[197] Reference Example 27
[198] 2-isopropylisonicotinic acid
[199] 7.5 ml of 8N aqueous solution of potassium hydroxide was added to 50 ml of an ethanol solution of 2.7 g of 4-cyano-2-isopropylpyridine, and the mixture was refluxed for 12 hours. After cooling to room temperature, water and diethyl ether are added to the reaction solution, and the aqueous layer is separated. The aqueous layer is acidified to pH 3 with 4N hydrochloric acid and saturated with sodium chloride. The mixture was extracted with a mixed solution of ethyl acetate-isopropanol (5: 1, v / v), dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain 3.1 g of the title compound.
[200] Reference Example 28
[201] 2- (2,2,2-Trifluoroethoxy) isonicotinic acid
[202] 7.5 g of 2-chloroisonicotinic acid, 16 g of potassium tert-butoxide and 100 ml of 2,2,2-trifluoroethanol are stirred in a sealed tube at 170 占 폚 for 5 days. After distilling off the solvent, water and 4N hydrochloric acid are added and extracted with chloroform. The solvent was washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The resulting crystals were washed with hexane to obtain 7.7 g of the title compound.
[203] Reference Example 29
[204] 6-methylaminonicotinic acid
[205] A solution of 10 g of 6-chloronicotinic acid and 27 ml of 40% methylamine aqueous solution in 20 ml of pyridine is heated in a sealed tube at 150 DEG C for 24 hours. After cooling to room temperature, water is added and the pH is adjusted to 3 with 1N aqueous hydrochloric acid solution. Precipitated crystals were collected by filtration to obtain 5.82 g of the title compound as off-white crystals.
[206] Reference Example 30
[207] Synthesis of 6-acetylmethylaminonicotinic acid
[208] 1.5 g of 6-methylaminonicotinic acid is heated under reflux for 1 hour and 30 minutes in 20 ml of acetic anhydride. The solvent was distilled off under reduced pressure, a saturated aqueous solution of sodium hydrogencarbonate was added, the aqueous layer was washed with ethyl acetate, and then adjusted to pH 3 with concentrated hydrochloric acid. After extraction with chloroform, the organic layer was washed and dried, and the solvent was distilled off under reduced pressure to obtain 280 mg of the title compound as white crystals.
[209] Reference Example 31-1
[210] Methyl 2-isopropoxyisonicotinate
[211] 5 g of 6-chloronicotinic acid, 6.5 g of sodium isopropoxide and 100 ml of isopropanol are stirred at 150 DEG C for 4 days in a sealed tube. After the solvent was distilled off, 200 ml of methanol and 5 ml of concentrated sulfuric acid were added and the mixture was refluxed for 15 hours. The solvent is concentrated, then chloroform is added and the mixture is washed with a saturated aqueous solution of sodium hydrogencarbonate. The solvent was distilled off and the resulting mixture was then subjected to silica gel column chromatography eluting with hexane-ethyl acetate (10: 1, v / v) to give 2.5 g of the crystals of the title compound.
[212] Reference Example 31-2 is synthesized in the same manner as in Reference Example 31-1.
[213] Methyl 2- (2-morpholinoethoxy) isonicotinate
[214] Reference Example 32-1
[215] Trans-4- (2,5-dimethylpiperazin-1-yl) -2-methoxybenzonitrile
[216] To 5 ml of THF were added 1.35 g of potassium-tert-butoxide and 0.48 ml of methanol, and the mixture was stirred for 30 minutes. Then, 934 mg of trans-4- (2,5-dimethylpiperazin-1-yl) -2-fluoromethylbenzonitrile synthesized in Example 1-4 was added, and the mixture was stirred at room temperature for 2 days. The organic layer was washed with water and then the solvent was distilled off. The resulting mixture was treated with silica gel column chromatography and eluted with ethyl acetate-methanol-28% aqueous ammonia (9: 1: 0.2, v / v / v) to give 900 mg of the title compound.
[217] Reference Example 32-2 and Reference Example 32-3 were synthesized in the same manner as in Reference Example 32-1.
[218] Reference Example 32-2
[219] Trans-4- (2,5-dimethylpiperazin-1-yl) -2- (2-methoxyethoxy) benzonitrile
[220] Reference Example 32-3
[221] Trans-4- (2,5-dimethylpiperazin-1-yl) -2- (2-morpholinoethoxy) benzonitrile
[222] The properties of Reference Examples 8 to 32 are shown in Table 6.
[223] The structures and physical properties of the above Reference Example compounds are shown in the following table.
[224] In the table, the symbols have the following meanings.
[225] Ref. No .: Reference Yes No
[226] DATA: Physical and Chemical Properties
[227] NMR: nuclear magnetic resonance spectrum
[228] (Unless otherwise noted, DMSOd ₆ , measured in TMS internal standard)
[229] MS: mass spectrometry value
[230] Me: methyl
[231] Et: ethyl
[232] Ph: phenyl
[233] Remark: It refers to a salt of the compound having R ² and R ³ (the compound not having any particular mention is a racemic or stereoisomer-free compound) or a salt thereof.
[234]
[235]
[236]
[237]
[238]
[239]
[240]
[241]
[242] Example 1-1
[243] Trans-4- (4-cyano-3-trifluoromethylphenyl) -4'-fluoro-2,5-dimethylpiperazine-1-carboxyanilide
[244] 300 mg of trans-4- (2,5-dimethylpiperazin-1-yl) -2-trifluoromethylbenzonitrile synthesized in Referential Example 1-1 was dissolved in 10 ml of dichloromethane, p-fluorobenzisocyanate 0.13 ml is added dropwise, and the mixture is stirred at room temperature for 1 hour. The reaction solution was washed with water and then the solvent was distilled off. The resulting residue was purified by silica gel column chromatography to obtain 390 mg of the title compound as a colorless oily substance from a chloroform-methanol (99: 1, v / v) eluate . Subsequently, crystallization was carried out in acetone-diisopropyl ether to obtain 165 mg as colorless crystals.
[245] Examples 1-2 to 1-56 were synthesized in the same manner as in Example 1-1.
[246] Example 2-1
[247] 4- (4-cyano-3-trifluoromethylphenyl) -2,5-dimethyl-N- (2-thienyl) piperazine-1-carboxamide
[248] 0.32 ml of 2-canoyl chloride was dissolved in 10 ml of acetonitrile, 0.49 ml of triethylamine was added thereto under ice-cooling, and 290 mg of sodium azide was added thereto, followed by stirring at room temperature for 3 hours. The reaction solution is poured into ice water and extracted with diethyl ether. The organic layer is washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain pale brown crystals.
[249] The obtained crystals were dissolved in 10 ml of toluene and stirred at 100 占 폚 for 3 hours. The reaction solution was allowed to cool, 10 ml of acetonitrile was added and then 450 mg of trans-4- (2,5-dimethylpiperazin-1-yl) -2-trifluoromethylbenzonitrile synthesized in Reference Example 1-1 Lt; / RTI > The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, washed sequentially with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried with sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and 504 mg of the title compound as pale yellow product was obtained from ethyl acetate-hexane (1: 1, v / v) eluate.
[250] Examples 2-2 to 2-10 were synthesized in the same manner as in Example 2-1.
[251] Example 3-1
[252] Trans-4- (4-cyano-3-trifluoromethylphenyl) -2,5-dimethyl-N-phenethylpiperazine-1-carboxamide
[253] 5 ml of acetonitrile, 0.17 ml of triethylamine and 0.26 ml of DPPA were added to 180 mg of hydrocinnamic acid, and the mixture was heated under reflux for 1.5 hours. The reaction solution was cooled, 280 mg of trans-4- (2,5-dimethylpiperazin-1-yl) -2-trifluoromethylbenzonitrile synthesized in Reference Example 1-1 was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 204 mg of the title compound as a colorless oily substance from ethyl acetate-chloroform (2: 1, v / v) eluate.
[254] Examples 3-2 to 3-4 are synthesized in the same manner as in Example 3-1.
[255] Example 4
[256] Trans-2 ', 4'-dibromo-4- (4-cyano-3-fluorophenyl) -2,5- dimethylpiperazine- 1-carboxanilide
[257] Dibromoaniline (300 mg) was dissolved in THF (10 ml), triphosgene (153 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 4 hours. Subsequently, 427 mg of trans-4- (2,5-dimethylpiperazin-1-yl) -2-fluorobenzonitrile synthesized in Reference Example 1-1 and 5 ml of a THF solution of 460 mg of triethylamine were added dropwise, Lt; / RTI > The solvent was distilled off, and the obtained residue was dissolved in ethyl acetate, washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 390 mg of the title compound as light yellow compound from chloroform-hexane (1: 1, v / v) eluate.
[258] Example 5-1
[259] Synthesis of trans-4- (4-cyano-3-trifluoromethylphenyl) -2,5-dimethyl-N- (1-methyl-1-phenylethyl) piperazine-
[260] 532 mg of DIBOC are dissolved in 10 ml of acetonitrile, 3 ml of an acetonitrile solution of 124 mg of DMAP and 235 mg of cumylamine is added dropwise, and the mixture is stirred at room temperature for 10 minutes. Then, 300 mg of trans-4- (2,5-dimethylpiperazin-1-yl) -2-trifluoromethylbenzonitrile synthesized in Reference Example 1-1 was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in ethyl acetate, washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous solution of sodium chloride, and dried with sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and 475 mg of the title compound was obtained from ethyl acetate-hexane (1: 1, v / v) eluate.
[261] Example 5-2 and Example 5-3 were synthesized in the same manner as in Example 5-1.
[262] Example 6-1
[263] (2R, 5S) -N- (2- bromo-4-pyridyl) -4- (4-cyano-3- trifluoromethylphenyl) -2,5-dimethylpiperazine-1-carboxamide
[264] Amino-2-bromopyridine was dissolved in 1.4 ml of pyridine, 2.0 g of phenyl chloroformate was added, and the mixture was stirred at room temperature for 4 days. 2 g of (2S, 5R) -4- (2,5-dimethylpiperazin-1-yl) -2-trifluoromethylbenzonitrile synthesized in Referential Example 11-1 was added and the mixture was stirred at 100 ° C for 1 hour and 30 minutes Lt; / RTI > After the solvent was distilled off, the residue was dissolved in ethyl acetate, washed with water and then saturated brine, and then dried over magnesium sulfate. The solvent was distilled off and the residue was then subjected to silica gel column chromatography to elute with chloroform-methanol (30: 1, v / v). The obtained fraction was crystallized from ethyl acetate-hexane to give 2.7 g .
[265]
[266] Examples 6-2 to 6-16 are synthesized in the same manner as in Example 6-1.
[267] Examples 6-13
[268] (6-methoxy-3-pyridyl) -2,5-dimethylpiperazine-1-carboxamide
[269]
[270] Example 7-1
[271] (2R, 5S) -4- (4-cyano-3- trifluoromethylphenyl) -N - [(6-methoxy-3-pyridyl) methyl] -2,5-dimethylpiperazin- Vox amide
[272] 700 mg of (2S, 5R) -trans-4- (2,5-dimethylpiperazin-1-yl) -2-trifluoromethylbenzonitrile and 274 mg of triethylamine were added to a solution of 252 mg of triphosgene in 10 ml of dichloromethane. A solution of 10 ml of dichloromethane was added and the mixture was stirred for 1 hour. A solution of 409 mg of 5-aminomethyl-2-methoxypyridine synthesized in Reference Example and 274 mg of triethylamine in 10 ml of dichloromethane was added dropwise, and the mixture was stirred at room temperature overnight. The solvent is distilled off, water is added to the obtained residue, and the mixture is extracted with ethyl acetate, followed by drying to distill off the solvent. The obtained residue was treated with silica gel column chromatography and eluted with chloroform-methanol (50: 1, v / v) to obtain 1.02 g of the title compound.
[273] Examples 7-2 to 7-11 are synthesized in the same manner.
[274] Example 8-1
[275] 3- (4-cyano-3-trifluoromethylphenyl) -N- (4-fluorophenyl) -5,5-dimethyl- 1 -imidazolidinecarboxamide
[276] 1.0 g of 1- [2- (4-cyano-3-trifluoromethylanilino) -1,1-dimethylethyl] -3- (4- fluorophenyl) urea synthesized in Reference Example 9-1 Dissolved in 10 ml of acetic acid, 0.4 ml of formalin is added, and the mixture is heated at 50 占 폚 for 2 hours. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography, and the compound obtained from the chloroform-methanol (30: 1, v / v) eluate was washed with diisopropyl ether to give 751 mg of the title compound .
[277] Example 8-2 was synthesized in the same manner as in Example 8-1.
[278] Example 9
[279] (4-cyano-3-trifluoromethylphenyl) -N- (4-fluorophenyl) -2,5-dimethylpiperazine] -sulfonamide
[280] 1.21 g of trans-4- (2,5-dimethylpiperazin-1-yl) -2-trifluoromethylbenzonitrile synthesized in Reference Example 1-1 and 2.05 g of sulfamide were heated in 15 ml of pyridine for 1.5 hours under reflux do. Then, 4.05 ml of 4-fluoroaniline was added, and the mixture was heated under reflux for 4 hours. The solvent was distilled off and the residue was purified by silica gel column chromatography to give 701 mg of the title compound from the toluene-ethyl acetate eluate.
[281] Example 10
[282] Trans-4'-amino-4- (4-cyano-3-trifluoromethylphenyl) -2,5- dimethylpiperazine- 1-carboxanilide
[283] 450 mg of trans-4- (4-cyano-3-trifluoromethylphenyl) -2,5-dimethyl-4'-nitropiperazine-1-carboxyanilide synthesized in Example 1-4 was dissolved in 8 ml of methanol 4 ml of water, 280 mg of iron powder and 30 mg of ammonium chloride are added, and the mixture is heated under reflux for 5 hours. 280 mg of iron powder and 30 mg of ammonium chloride are added to the reaction solution, and the mixture is heated under reflux for 2 hours. The reaction solution is filtered using celite, and the solvent in the filtrate is distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed sequentially with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol-chloroform) to obtain 260 mg of the title compound as colorless crystals.
[284] Example 11
[285] Trans-4'-acetamino-4- (4-cyano-3-trifluoromethylphenyl) -2,5-dimethylpiperazine-1-carboxyanilide
[286] 300 mg of trans-4'-amino-4- (4-cyano-3-trifluoromethylphenyl) -2,5-dimethylpiperazine-1-carboxyanilide synthesized in Example 10 and 88 mg of acetic anhydride were dissolved in dichloroethane And the mixture was stirred at room temperature for 10 hours. After the solvent was distilled off, the residue was dissolved in ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized from ethyl acetate-hexane to give 195 mg of the title compound as colorless crystals.
[287] Example 12-1
[288] (4-cyano-3-trifluoromethylphenyl) -2,5-dimethylpiperazine-1-carbonyl] amino] pyridine-2-carboxylic acid
[289] (2R, 5S) -4 - [[4- (4-cyano-3-trifluoromethylphenyl) -2,5-dimethylpiperazine- 1-carbonyl] amino] pyridine -2-carboxylate in 40 ml of THF, 40 ml of a 1N sodium hydroxide aqueous solution was added dropwise, and the mixture was stirred at room temperature for 1 hour. 4N hydrochloric acid was added under ice-cooling to adjust the pH to 2 to 3, and the resulting precipitate was collected by filtration, washed with purified water and then dried under reduced pressure at 70 ° C to obtain 2.80 g of the title compound.
[290] Example 12-2 and Example 12-3 are synthesized in the same manner.
[291] Example 13-1
[292] (2R, 5S) -4- (4-cyano-3-trifluoromethylphenyl) -2,5-dimethyl-N- (2- methylcarbamoyl-4-pyridyl) piperazine-
[293] (2R, 5S) -4 - [[4- (4-cyano-3-trifluoromethylphenyl) -2,5-dimethylpiperazine-1- carbonyl] amino] pyridine prepared in Example 12-1 Carboxylic acid To a suspension of 1.10 g of DMF in 30 ml of DMF, 332 mg of HOBt and 519 mg of WSC were added successively under ice-cooling, the temperature was raised to room temperature, and the mixture was stirred for 1.5 hours. After ice-cooling again, 10 ml of 40% methylamine aqueous solution was added all at once and stirred overnight. Purified water was added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and 674 mg of the title compound was obtained from a methanol-ethyl acetate (1: 9, v / v) eluate.
[294]
[295] Examples 13-2 to 13-4 are synthesized in the same manner.
[296] Example 14
[297] Trans-4- (4-cyano-3-trifluoromethylphenyl) -2,5-dimethyl-4 '-( methylamino) sulfonylpiperazine-1-carboxyanilide
[298] To a solution of trans-4- (2,5-dimethylpiperazin-1-yl) -2-trifluoroacetic acid synthesized in Reference Example 1-1 at -78 ° C was dissolved 200 mg of 4-chlorosulfonylphenyl isocyanate in 20 ml of dichloromethane. 5 ml of a dichloromethane solution containing 400 mg of methylbenzonitrile was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Subsequently, 400 mg of a 40% methylamine methanol solution was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, the residue was dissolved in ethyl acetate, washed sequentially with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and 340 mg of the title compound was obtained from ethyl acetate-hexane (1: 1, v / v) eluate.
[299] Example 15-1
[300] Trans-4- (4-cyano-3-trifluoromethylphenyl) -4'-fluoro-N, 2,5-trimethylpiperazine-1-carboxyanilide
[301] To a solution of trans-4- (4-cyano-3-trifluoromethylphenyl) -4'-fluoro-2,5-dimethyl Piperazine-1-carboxyanilide, and the mixture was stirred at 50 DEG C for 10 minutes. The reaction solution was ice-cooled, 0.11 ml of methyl iodide was added dropwise, and the mixture was stirred at room temperature for 2 hours. Water is added to the reaction solution, which is extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and 620 mg of the title compound was obtained from the ethyl acetate-hexane eluate.
[302] Example 15-2 and Example 15-3 were synthesized in the same manner as in Example 15-1. In Example 15-2, acetic anhydride is used instead of methyl iodide.
[303] Example 16-1
[304] 4- [1-oxo-4-thiomorpholine-4-carbonyl) piperazin-1-yl] -2-trifluoromethylbenzonitrile
[305] 270 mg of 4- [2,5-dimethyl-4- (thiomorpholine-4-carbonyl) piperazin-1-yl] -2-trifluoromethylbenzonitrile synthesized in Example 7-6 was dissolved in 7 ml 110 mg of sodium hydrogencarbonate and 155 mg of metachloroperbenzoic acid (MCPBA) were added at -78 ° C, and the mixture was stirred at the same temperature for 6 hours. Chloroform is added to the reaction solution, and the mixture is washed with 1N aqueous sodium hydroxide solution and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 232 mg of the title compound from methanol-chloroform (1: 50, v / v) eluate.
[306] Examples 16-2 to 16-5 are synthesized in the same manner as in Example 16-1. Further, the amount of MCPBA to be used is appropriately adjusted according to the oxidation state of the product.
[307] Example 17
[308] 4- [4-benzyloxycarbonyl-2-methyl-1-piperazinyl] -2-trifluoromethylbenzonitrile
[309] Fluoro-2-trifluoromethylbenzonitrile (814 mg) and potassium carbonate (2.38 g) were added to DMF (20 m) and the mixture was stirred at 100 占 폚 for 20 hours Lt; / RTI > Water is added, and the mixture is extracted with ethyl acetate. After drying, the solvent is distilled off. The obtained residue was purified by silica gel column chromatography to obtain 440 mg of the title compound from ethyl acetate-hexane (3: 1, v / v) eluate.
[310] Example 18-1
[311] (2R, 5S) -trans-4- (4-cyano-3-trifluoromethylphenyl) amides
[312] 3.4 g of 2-chloroisonicotinic acid was suspended in 50 ml of acetonitrile, 2.64 ml of oxalyl chloride and 3 drops of DMF were added, and the mixture was stirred at room temperature for 40 minutes. Subsequently, 2.81 g of sodium azide and 9.03 ml of triethylamine were added, and the mixture was stirred at room temperature for 1 hour. Water is added to the reaction solution, which is then extracted with ether, and then the solvent is distilled off to obtain a crude acid azide. This compound was dissolved in 30 ml of toluene and heated under reflux for 45 minutes. To the resulting solution was added dropwise a solution of (2S, 5R) -4- (2,5-dimethylpiperazin-1-yl) 2 g of romethylbenzonitrile is added and the mixture is stirred for 30 minutes. After the solvent was distilled off, the resulting mixture was treated with silica gel column chromatography and eluted with chloroform-methanol (50: 1, v / v) to give 3.44 g of the title compound. Crystallization was then carried out in ethyl acetate-hexane to give 2.51 g of the title compound crystals.
[313]
[314] Next, the racemic or corresponding optically active trans-4- (2,5-dimethylpiperazin-1-yl) -2-trifluoromethylbenzonitrile, trans-2- Yl) -2-trifluoromethylbenzonitrile or trans-4- (2,5-dimethylpiperazin-1-yl) - Synthesis of Example 18-2 to Example 18-30 was carried out in the same manner as in Example 18-1 using 2- (2-morpholinoethoxy) benzonitrile. Some compounds are isolated as hydrochlorides according to conventional methods.
[315] Example 18-2
[316] (2R, 5S) -4- (4-cyano-3-trifluoromethylphenyl) -2,5-dimethyl-N- (4- pyridyl) piperazine- 1 -carboxamide monohydrochloride
[317]
[318] Example 18-4
[319] (6R, 5S) -4- (4-cyano-3-trifluoromethylphenyl) -2,5-dimethyl-N- (6-trifluoromethyl-3-pyridyl) piperazin- amides
[320]
[321] Examples 18-5
[322] (6-fluoro-3-pyridyl) -2,5-dimethylpiperazine-1-carboxamide
[323]
[324]
[325] Examples 18-7
[326] (2R, 5S) -N- (6-cyano-3-pyridyl) -4- (4- cyano-3- trifluoromethylphenyl) -2,5- dimethylpiperazine-1-carboxamide
[327]
[328] Example 18-8
[329] (2R, 5S) -4- (4-cyano-3- trifluoromethylphenyl) -N- (2- fluoro-4-pyridyl) -2,5- dimethylpiperazine- 1-carboxamide
[330]
[331] Examples 18-9
[332] (2R, 5S) -4- (4-cyano-3-trifluoromethylphenyl) -2,5-dimethyl-N- (2-trifluoromethyl-4- pyridyl) piperazin- amides
[333]
[334] Example 19-1
[335] (2R, 5S) -4- (4-cyano-3-trifluoromethylphenyl) -N- (2- methoxy-6-methyl-4-pyridyl) -2,5-dimethylpiperazin- Carboxamide
[336] To a solution of 2-methoxy-6-methyl-4-pyridinecarboxylic acid ethyl ester (1.20 g) in THF (10 ml) was added 6.1 ml of a 1N sodium hydroxide aqueous solution and the mixture was stirred at room temperature for 1 hour and 20 minutes. -6-methyl-4-pyridinecarboxylic acid sodium salt. Subsequently, by the same procedure as in Example 18-1, the title compound was obtained.
[337]
[338] In the same manner as in Example 19-2 to Example 19-6, synthesis was carried out.
[339] Example 19-2
[340] (2-ethyl-6-methoxy-4-pyridyl) -2,5-dimethylpiperazin-l- Carboxamide
[341]
[342] Example 20
[343] (2R, 5S) -N- (2- acetyl-4-pyridyl) -4- (4-cyano-3- trifluoromethylphenyl) -2,5-dimethylpiperazine-1-carboxamide
[344] To a solution of 1.41 g of 2-acetyl-4-pyridinylcarbamic acid tert-butyl ester in 12.5 ml of chloroform was added 12.5 ml of trifluoroacetic acid under ice-cooling with stirring. Immediately, the temperature is raised to room temperature and stirred for 2 hours and 40 minutes. The solvent was distilled off under reduced pressure to obtain a crude amine. This compound is dissolved in 25 ml of pyridine, 0.83 ml of phenyl chloroformate is added under ice-cooling and the temperature is immediately raised to room temperature. After 8 hours and 30 minutes, a solution of 1.4 g of (2S, 5R) -4- (2,5-dimethylpiperazin-1-yl) -2-trifluoromethylbenzonitrile in 10 ml of pyridine was added, Reflux. After cooling to room temperature, water is added to the reaction solution and extracted with chloroform. The organic layer is washed with a saturated saline solution, dried using anhydrous sodium sulfate, and then the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 1.03 g of the title compound from a methanol-chloroform (1: 99, v / v) eluate.
[345]
[346]
[347] Example 21
[348] (2R, 5S) -N- (2-amino-4-pyrimidyl) -4- (4-cyano-3- trifluoromethylphenyl) -2,5-dimethylpiperazine-
[349] Synthesis of (2R, 5S) -4- (4-cyano-3-trifluoromethylphenyl) -N- [2- (1,1- dimethylethoxycarbonyl) amino- Pyrimidyl] -2,5-dimethylpiperazine-1-carboxamide in 60 ml of dichloroethane was added 15 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for about 12 hours. The reaction solution is distilled off under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate is added to the obtained residue, followed by extraction with chloroform. The obtained organic layer was washed with water and then dried over anhydrous magnesium sulfate to distill off the solvent. The obtained crude product was treated with silica gel column chromatography to obtain the title compound from the eluate of chloroform-methanol (30: 1, v / v) g. Subsequently, crystallization with ethyl acetate-hexane gave 1.51 g of the title compound as crystals.
[350]
[351] Example 22-1
[352] (+/-) -trans-N- (2-acetylamino-4-pyrimidyl) -4- (4- cyano-3- trifluoromethylphenyl) -2,5-dimethylpiperazine- amides
[353] (+/-) -trans-N- (2-amino-4-pyrimidyl) -4- (4-cyano-3- trifluoromethylphenyl) -2,5-dimethyl Piperazine-1-carboxamide in 10 ml of pyridine, 1.2 ml of acetic anhydride was added, and the mixture was stirred at room temperature for about 12 hours and then heated at 70 ° C for about 1 hour. The reaction solution was distilled off under reduced pressure, and a 0.5N sodium hydroxide aqueous solution was added to the obtained residue, followed by extraction with chloroform. The obtained organic layer was washed with water and then dried over anhydrous magnesium sulfate to distill off the solvent. The obtained crude product was isolated by silica gel column chromatography and eluted with chloroform-methanol-28% aqueous ammonia (500: 9: 1, v / v / v) From the eluate 0.46 g of the title compound is obtained. Further, crystallization was carried out with an ethyl acetate-hexane solution to obtain 0.31 g of white crystals.
[354] Example 22-2 was synthesized in the same manner.
[355] Example 23-1
[356] (+/-) - trans-N- (2-amino-4-pyridyl) -4- (4-cyano-3- trifluoromethylphenyl) -2,5- dimethylpiperazine- 1-carboxamide
[357] (+/-) -trans-4 - [[4- (4-cyano-3-trifluoromethylphenyl) -2,5-dimethylpiperazine-1-carbonyl ] Amino] pyridine-2-carboxylic acid, 1.5 ml of DPPA and 1.5 ml of triethylamine in 50 ml of t-butanol is heated under reflux for 8 hours, and the solvent is distilled off under reduced pressure. 30 ml of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the mixture was made alkaline with a saturated aqueous sodium hydrogencarbonate solution. Subsequently, the mixture is extracted with ethyl acetate, the organic layer is washed with purified water and then with saturated brine, dried over anhydrous sodium sulfate, and then the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and 0.94 g of the title compound was obtained from chloroform-methanol (10: 1, v / v) eluate. Crystallization in ethyl acetate-hexane gave 0.72 g of the title compound as white crystals.
[358] Example 23-2 was synthesized in the same manner.
[359] Example 24
[360] (6-aminosulfonyl-3-pyridyl) -4- (4-cyano-3- trifluoromethylphenyl) -2,5-dimethylpiperazine-1-carboxamide
[361] 4- (4-cyano-3-trifluoromethylphenyl) -N- (6-methanesulfonyl-3-pyridyl) -2,5-dimethylpiperazine- 1-carboxamide A solution of 2.48 g of THF 7.3 ml of a 1.54 M pentane solution of tert-butyllithium was added dropwise at -78 占 폚 and stirred at -30 占 폚 for 15 minutes. After cooling again to -78 ° C, 15.5 ml of a 1.0 M tetrahydrofuran solution of tri-n-butylborane was added, the temperature was raised to room temperature over 1 hour, and the mixture was heated under reflux for 18 hours. 5.91 g of sodium acetate, 50 ml of water and 491 mg of hydroxylamine-0-sulfonic acid were added under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction solution is extracted with ethyl acetate, and the organic layer is successively washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and then the solvent is distilled off. The resulting mixture was treated with silica gel column chromatography and eluted with chloroform-methanol (9: 1, v / v) to give 414 mg of the title compound. Subsequently, crystallization was carried out twice in ethanol to obtain 271 mg of crystals of the title compound.
[362] In addition, the compounds of Examples 25 to 28 can be synthesized in the same manner by applying the production method disclosed in the specification or the conventional synthesis method in addition to the above-mentioned examples.
[363] The structures and physical properties of the above-mentioned examples are described in the following table.
[364] The symbols in the table have the same meanings as those in the table of the reference example, and the other symbols have the following meanings.
[365] Ex .: Example No. Qy: Quinolyl
[366] DATA: Physical and chemical properties Mor: Morpholyl
[367] mp: melting point 占 폚 (recrystallization solvent) AcOEt: ethyl acetate
[368] MS: mass spectrometry EtOH: ethanol
[369] i-Pr: isopropyl (Et) ₂ O: diethyl ether
[370] t-Bu: t-butyl 1,2-diCl-Et: 1,2-dichloroethane
[371] Ac: acetyl (i-Pr) ₂ 0: diisopropyl ether
[372] c-Pr: cyclopropyl MeOH: methanol
[373] Py: pyridyl iPrOH: isopropanol
[374] Pm: pyrimidyl Hex: hexane
[375] Im: imidazole
[376]
[377]
[378]
[379]
[380]
[381]
[382]
[383]
[384]
[385]
[386] Effects of the Invention
[387] The compound of the present invention specifically binds to the androgen receptor and has a strong anti-androgen action. In addition, it has little effect on the blood sex hormone, and is a useful compound as a strong antiandrogen agent.
[388] Therefore, the compound of the present invention is useful as a therapeutic agent or prophylactic agent for prostate cancer, hyperplasia of the prostate, masculinosis, hyperhidrosis, baldness, ache, bruise and the like.
[389] The usefulness of the compounds of the present invention is confirmed by the following test methods.
[390] Evaluation of binding activity to rat androgen receptor
[391] (1) Preparation of cytosolic fraction of rat prostate
[392] Twenty-four hours after the testis is removed, the abdominal prostate is removed from a 20 week old male Wistar rat. After homogenization and centrifugation at 800 × g × 20 minutes, the supernatant is centrifuged again for 223,000 × g × 60 minutes and the supernatant is recovered to obtain a cytoplasmic fraction.
[393] (2) Measurement of specific binding of ³ H-miboloreon to prostate cytoplasmic androgen receptor
[394] The cytosolic fraction obtained in (1) was prepared at a protein concentration of 1 mg / ml as a rat androgen receptor solution. ³ H-mibolerone, triamcinolone acetate, and dimethylsulfoxide (DMSO) are added to 400 μl of the rat androgen receptor solution to a final concentration of 1 nM, 1 μM, and 5%, respectively, to a final volume of 0.5 ml. After standing at 4 캜 for 18 hours, 500 ㎕ of a solution containing 0.05% dextran-T70 and 0.5% Dulco G-60 was added and mixed, and the mixture was allowed to stand at 4 캜 for 15 minutes The supernatant is recovered by centrifugation. A mixture of bio-flow (Bioflow) the recovered supernatant was added 5ml 600㎕ then, by measuring the radioactivity determined on the total combined amount of ³ H- US bolre theory for the rat androgen receptor. The non-specific binding amount is determined in the same manner as above except that a DMSO solution containing unlabeled miVoleron is substituted for DMSO so that the final concentration of unlabelled miVoleron becomes 40 μM. The difference between the total binding amount and the non-specific binding amount is defined as the specific binding amount bound to the androgen receptor.
[395] (3) Inhibitory activity of the compound of the present invention on the specific binding of ³ H-mibolerone
[396] The DMSO solution containing the compound of the present invention was added at the same time as the ^3- H-mibolerone by changing the concentration and reacted in the same manner as in (2) to obtain a ³ H-Mibolore conjugated to the rat androgen receptor Determine the specific binding of Ron. From these values and the values obtained in (2), the IC ₅₀ of the inhibitory activity of the compound of the present invention against the specific binding of ³ H -mvolylon is obtained. Further, the dissociation constant Ki is determined from the IC ₅₀ by the general formula ^* of Cheng and Prusoff.
[397] ^* : Cheng YC and Prusoff WH, Relationship between the inhibition constant (Ki) and the concentration of inhibitor which cause 50% inhibition of an enzymatic reaction., Biochem. Pharmacol., 22, 3099 (1973)
[398] Experimental results of the compound of the present invention are shown in the following table.
[399] compound Binding activity to rat androgen receptor (K _i = nM) room city Yes 6-1 7.56 6-13 3.58 13-1 1.91 18-4 5.01 18-7 6.66 18-8 15.6 21 1.81
[400] From the above test results, it was confirmed that the compound of the present invention specifically binds to the androgen receptor and inhibits the binding of the androgen receptor to the androgen receptor.
[401] Prostatectomy for mature male rats
[402] For male Wistar rats of 10 weeks of age, the compound of the present invention is suspended in a 0.5% methylcellulose solution and orally administered once a day for 15 days continuously. After 6 hours of the final administration, the wet weight (weight) of the abdominal prostate is measured to examine the prostate scarring action of the compound of the present invention.
[403] The prostate scarring effect of the compound of the present invention was evaluated by comparing the group administered with the compound of the present invention as a test group, the group administered with methylcellulose alone as a control group, the group administered with methylcellulose only immediately before administration, It is calculated by a formula.
[404] Reduction ratio (%) = 100 (B-A) / (B-C)
[405] A: Abdominal wet weight of the test group
[406] B: Wet weight of the control abdomen prostate
[407] C: Wet weight of abdomen prostate in castration group
[408] The ED ₅₀ value is calculated from the obtained reduction ratio by linear regression.
[409] According to the above test results, the ED ₅₀ of the compound shown in Table 11 is 0.3 to 11 mg / kg, and exhibits about 2- to 60-fold higher activity than bicalutamide having the most potent action among currently used anti-androgens.
[410] Therefore, the compound of the present invention has a powerful androgen receptor inhibitory action and a very excellent prostate-reducing action of mature male rats, and is useful as a preventive and therapeutic agent for diseases such as prostate cancer, hypertrophy, menstrual hyperhidrosis, baldness, And is useful as a therapeutic agent for such diseases.
[1] The present invention relates to novel cyanophenyl derivatives, salts thereof and pharmaceutical compositions useful as medicaments, particularly antiandrogen drugs.

权利要求:
Claims (7)
[1" claim-type="Currently amended] A cyanophenyl derivative of the formula (I) or a salt thereof.
Formula I

In the above formula (I)
R is a cyano or nitro group,
R ¹ is a hydrogen atom, a halogen atom, cyano, halogeno lower alkyl, nitro, carboxyl, lower alkyl, R ⁶ -A-, R ⁷ -S (O) _p- , Lower alkyl-OC (= O) - group,
R ² , R ³ and R ⁴ are the same or different and represent a hydrogen atom, a lower alkyl group, a carbamoyl group which may be substituted by one or two lower alkyl groups, a lower alkyl-C (= O) (= O) - group, R ² and R ³ are bonded to any carbon atom on the ring,
R ⁵ is selected from the group consisting of lower alkyl, aryl-lower alkyl-O-, carboxyl, lower alkyl-O-C (= O) -, an amide which may be substituted with one or two lower alkyl groups, or a ring or a cycloalkyl ^{group, N (R 13) R 14} - is a lower alkyl -O-, only when m is 1, R ⁴ and R ⁵ are integrally 5 members which may have other hetero atom or a 6-membered heteroaryl Can form a ring,
R ⁶ is halogeno lower alkyl or aryl, N (R ⁹⁾ and R ^10, 0H or lower alkyl which may be substituted with a lower alkyl -O-,
R ⁷ is lower alkyl, aryl or N (R ¹¹ ) R ¹² -
R ^8, R ^9, R ^10, R ^11, R ^12, R ¹³ and R ¹⁴ is hydrogen, lower-alkyl or aryl, with the proviso that R ⁶ and R ^8, R ⁹ and R ¹⁰ or R ¹³ and R ¹⁴ are integral respectively To form a nitrogen-containing cycloalkyl which may have another heteroatom and may have a substituent,
k or n is 1, 2 or 3,
m is 0 or 1,
p is 0, 1 or 2,
A is an oxygen atom or NR < ⁸ >
X is -C (= O) -, -C (= S) - or -S (O) ₂ - group, and
Y is a bond, lower alkylene, -C (= O) - or -S (O) ₂ - group, provided that when R ⁵ is a lower alkyl group, Y is a group other than lower alkylene,
Z ₁ or Z ₂ are the same or different and each is CH or a nitrogen atom, provided that when R ¹ is a hydrogen atom, at least one of R ² and R ³ is lower alkyl.
[2" claim-type="Currently amended] The cyanophenyl derivative or a salt thereof according to claim 1, wherein R is a cyano group.
[3" claim-type="Currently amended] The compound according to claim 2, wherein R ¹ is a halogen atom, cyano, halogeno lower alkyl, nitro or lower alkyl-O-, at least one of R ² and R ³ is a lower alkyl group, R ⁴ is a hydrogen atom or a lower alkyl group R ⁵ is an aryl, heterocyclic or cycloalkyl group which may have a substituent, k is 2, n is 1, m is 1, X is a -C (= O) - group, Y is a bond , Z < _{1 >} or Z < _{2 >} are both CH, or a salt thereof.
[4" claim-type="Currently amended] The compound according to claim 3, wherein the substituent of the aryl, heterocyclic or cycloalkyl group which may have a substituent on R ⁵ is a halogen atom, halogeno lower alkyl, lower alkyl, lower alkyl-O-, lower alkyl- S (O) -, lower alkyl-S (O) ₂ -, sulfamoyl which may be substituted by one or two lower alkyl, halogeno lower alkyl-O-, cyano, nitro, oxo (= O) -, aryl-C (= O) -, one or two lower alkyl or lower alkyl-C (= O) - or lower alkyl-OC A group selected from the group consisting of amino, aryl-O-, amino-O-, carbamoyl which may be substituted by lower alkyl, carboxyl, lower alkyl-OC (= O) -, heterocycle and OH group.
[5" claim-type="Currently amended] (6-methoxy-3-pyridyl) -2,5-dimethylpiperazine-1-carboxamide, (2R, 5S) -N- (2-amino-4-pyrimidyl) -4- (4-cyano-3- trifluoromethylphenyl) -2,5-dimethylpiperazine-1-carboxamide, 2R, 5S) -4- (4-cyano-3-trifluoromethylphenyl) -2,5-dimethyl-N- (6-trifluoromethyl-3-pyridyl) piperazine- , (2R, 5S) -4- (4-cyano-3- trifluoromethylphenyl) -N- (2- fluoro-4-pyridyl) -2,5-dimethylpiperazine-1-carboxamide 4-pyridyl) -4- (4-cyano-3-trifluoromethylphenyl) -2,5-dimethylpiperazine-1-carboxamide ≪ / RTI > or a salt thereof.
[6" claim-type="Currently amended] A pharmaceutical composition comprising the cyanophenyl derivative or a salt thereof according to Claim 1 as an active ingredient.
[7" claim-type="Currently amended] The pharmaceutical composition according to claim 6, which is an anti-androgen agent.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1998-09-22|Priority to JP26750898

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1998-09-22|Priority to JP98-267508

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1999-06-02|Priority to JP15539899

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1999-06-02|Priority to JP99-155398

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1999-09-21|Application filed by 오노다 마사요시, 야마노우치세이야쿠 가부시키가이샤

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2001-08-09|Publication of KR20010075268A

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2006-12-22|Application granted

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2006-12-22|Publication of KR100660309B1

优先权:

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申请号 | 申请日 | 专利标题

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JP26750898|1998-09-22|

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JP98-267508|1998-09-22|

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JP15539899|1999-06-02|

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JP99-155398|1999-06-02|